title: Oligodendrocyte differentiation and signaling after transferrin internalization: a mechanism of action.
abstract: Oligodendrocytes are the cells producing the myelin membrane around the axons in the central nervous system and, although apotransferrin (aTf) is required for oligodendrocyte differentiation, the underlying mechanisms are not fully understood. Fyn tyrosine kinase, a member of the Src family of proteins, has been shown to play an important role in myelination by up-regulating the expression of myelin basic protein; however, a molecular link between aTf and Fyn kinase signaling pathway during oligodendrocytes differentiation has not been established yet. Our aim was to investigate whether Fyn kinase, MEK/ERK and PI3K/Akt signaling pathways are required for aTf-stimulation of oligodendrocyte differentiation and also to determine if the transferrin receptor is involved in these mechanisms. Treatment of primary cultures of oligodendroglial precursor cells with aTf leads to Fyn kinase activation by a mechanism that involves transferrin receptor. In turn, Fyn kinase activation promotes MEK-mediated transient phosphorylation of ERK1/2. On the other hand, transferrin receptor internalization also produces rapid and sustained activation of Akt, which involves phosphatidylinositol 3-kinase (PI3K) activation. Finally, aTf incorporated through clathrin-mediated endocytosis increases myelin basic protein, F3-contactin and β-tubulin through Fyn/MEK/ERK pathways, as well as an activation of the PI3K/Akt pathway. Our results also demonstrate that the activation of the pathways necessary for oligodendroglial precursor cell maturation is dependent on AP2 recruitment onto the plasma membrane for clathrin-mediated endocytosis of transferrin receptor.
authors.affiliation: Cátedra de Química Biológica Patológica, Departamento de Química Biológica, Facultad de Farmacia y Bioquímica (FFyB), Universidad de Buenos Aires (UBA), Instituto de Química y Fisicoquímica Biológica "Prof. Alejandro C. Paladini" (IQUIFIB), UBA-Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Junin 965, CABA, Buenos Aires, Argentina. Electronic address: mjuliaperez@gmail.com.
authors.forename: María Julia
authors.initials: MJ
authors.lastname: Pérez
authors.forename: Natalia
authors.initials: N
authors.lastname: Fernandez
authors.forename: Juana María
authors.initials: JM
authors.lastname: Pasquini
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D002966:Clathrin / Q000378:metabolism; D005260:Female; D020935:MAP Kinase Signaling System / Q000502:physiology; D008297:Male; D009836:Oligodendroglia / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt; D051076:Proto-Oncogene Proteins c-fyn / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D011990:Receptors, Transferrin / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D014168:Transferrin / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D002966:Clathrin; D011990:Receptors, Transferrin; D014168:Transferrin; D019869:Phosphatidylinositol 3-Kinases; D051076:Proto-Oncogene Proteins c-fyn; D051057:Proto-Oncogene Proteins c-akt
keywords: Ab-TfR; Cyt B; DIII; DIIIΔ2; EH29; F3; F3-contactin; Fyn; Fyn tyrosine kinase; GAPDH; LY; LY294002, PI3 kinase inhibitor; MBP; MDC; MEK/ERK pathways; MEK1/2 inhibitor; NG2; OL; OPC; Oligodendrocyte differentiation and transferrin; PD; PD98059, MEK1/2 inhibitor; PDGFR-α; PI3K; PI3K/Akt pathway; PP2; Src family of tyrosine kinases inhibitor; Texas Red-labeled transferrin; Tf; Tf-TR; TfR; U0126; WM; aTf; apotransferrin; cytochalasin B; glyceraldehyde 3-phosphate dehydrogenase; mouse antibody against Tf receptor (Ab-2) clone 42/6; myelin basic protein; nerve/glia antigen 2; oligodendrocyte progenitor cell; oligodendrocytes; pEGFP-C2-Eps15 DIII plasmid, Eps15 dominant negative mutant; pEGFP-C2-Eps15 DIIIΔ2 plasmid, Eps15 irrelevant mutant; pEGFP-C2-Eps15 EH29 plasmid, Eps15 dominant negative mutant; phosphatidylinositol 3-kinase; platelet-derived growth factor α; primary amine monodansylcadaverin; transferrin; transferrin receptor; wortmannin, PI3 kinase inhibitor; β-tub; β-tubulin